RESUMEN
Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.
Asunto(s)
Proteína de Unión a CREB , Proteínas de Choque Térmico , Trastornos del Neurodesarrollo , Síndrome de Rubinstein-Taybi , Factores de Transcripción , Humanos , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Histonas/genética , Mutación , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína p300 Asociada a E1A/genética , Proteína p300 Asociada a E1A/metabolismoRESUMEN
Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post-translational modifications, and HSF2 steers the formation of atypical alcohol-specific HSF1-HSF2 heterocomplexes. This perturbs the in vivo binding of HSF2 to heat shock elements (HSEs) in genes that control neuronal migration in normal conditions, such as p35 or the MAPs (microtubule-associated proteins, such as Dclk1 and Dcx), and alters their expression. In the absence of HSF2, migration defects as well as alterations in gene expression are reduced. Thus, HSF2, as a sensor for alcohol stress in the fetal brain, acts as a mediator of the neuronal migration defects associated with FASD.
Asunto(s)
Trastornos del Espectro Alcohólico Fetal/patología , Proteínas de Choque Térmico/metabolismo , Malformaciones del Desarrollo Cortical del Grupo II/inducido químicamente , Estrés Fisiológico , Factores de Transcripción/metabolismo , Animales , Corteza Cerebral/patología , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Proteína Doblecortina , Regulación de la Expresión Génica , Factores de Transcripción del Choque Térmico , Proteínas de Choque Térmico/deficiencia , Ratones , Ratones Noqueados , Unión Proteica , Factores de Transcripción/deficienciaRESUMEN
Heat shock factors form a family of transcription factors (four in mammals), which were named according to the first discovery of their activation by heat shock. As a result of the universality and robustness of their response to heat shock, the stress-dependent activation of heat shock factor became a 'paradigm': by binding to conserved DNA sequences (heat shock elements), heat shock factors trigger the expression of genes encoding heat shock proteins that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stress and in several pathological conditions. Besides their roles in the stress response, heat shock factors perform crucial roles during gametogenesis and development in physiological conditions. First, during these process, in stress conditions, they are either proactive for survival or, conversely, for apoptotic process, allowing elimination or, inversely, protection of certain cell populations in a way that prevents the formation of damaged gametes and secure future reproductive success. Second, heat shock factors display subtle interplay in a tissue- and stage-specific manner, in regulating very specific sets of heat shock genes, but also many other genes encoding growth factors or involved in cytoskeletal dynamics. Third, they act not only by their classical transcription factor activities, but are necessary for the establishment of chromatin structure and, likely, genome stability. Finally, in contrast to the heat shock gene paradigm, heat shock elements bound by heat shock factors in developmental process turn out to be extremely dispersed in the genome, which is susceptible to lead to the future definition of 'developmental heat shock element'.